Immunoglobulins are typically composed of two fundamental domains, the constant domain (Fc) and the variable domain. While the variable domain interacts with target antigens, the constant domain mediates a variety of biological events by interacting with other proteins of the host organism. Receptors for the Fc portion of IgG, Fcγ receptors, play an essential role in the protection of the organism against foreign antigens by removing antigen-antibody complexes from the circulation. Receptors are present on monocytes, macrophages, neutrophils, natural killer (NK) cells, platelets, and T and B lymphocytes, and they participate in diverse functions such as phagocytosis of immune complexes, NK cell ADCC, platelet activation, and modulation of antibody production by B cells.
Fcγ receptors also play a role in a number of diseases characterized by a hyperactive immune system or other undesirable immunological activity. Fcγ receptors participate in a number of autoimmune and inflammatory diseases. As an example, Fcγ receptors are implicated in immune thrombocytopenia. The pathogenic mechanism of immune thrombocytopenia involves antibody-mediated destruction of platelets in the reticuloendothelial system through Fcγ receptors (FcγRs) expressed on tissue macrophages, particularly in the spleen and liver. FcγRs signal via immunoreceptor tyrosine-based activation motifs (ITAMs) that are located either in the cytosolic domains of the receptors themselves (FcγRIIA), or within associated γ (FcγRI and FcγRIIIA) or ζ (FcγRIIIA) subunits. Following clustering of the FcγRs and their associated γ subunits by bound IgG ligands, tyrosine residues within the ITAMs become phosphorylated. The tyrosine-phosphorylated residues of the ITAMs serve as high affinity binding sites for Syk, a tyrosine kinase that contains tandem SH2 domains, which propagates intracellular signaling processes. In humans, FcγRIIA and FcγRIII are the primary activating receptors.
The FcγRIIB receptor has an inhibitory role. FcγRIIB recruits the SHIP kinase and abrogates signaling triggered by activating Fcγ receptors. The overall cellular response depends in part on the ratio of signaling mediated by inhibiting and activating receptors.
An object of the present disclosure is to provide nucleic acid agents that inhibit FcγRIIA expression and to provide methods of using such agents for therapeutic purposes.